cosyntropin and Disorders-of-Sex-Development

The 46,XX disorders of sex development (DSDs) cause virilisation or masculinisation of the female foetus. The final common pathway of all 46,XX DSDs is excess dihydrotestosterone (DHT) or potent foreign androgen in the genital tissue during the critical period of sexual differentiation. Whereas the foetal testis is source of androgen in the male, it is the foetal adrenal that produces the DHT precursors in the female. By understanding the principles of human steroid biosynthesis, the pathogenesis of each disorder may be logically deduced, and treatment strategies are rationally constructed. In practice, however, therapies for many of these diseases are fraught with complications and caveats, and current approaches leave much room for improvement. This review discusses these diseases, their pathogenesis and approaches to therapy. We emphasise areas where improved treatments are sorely needed.

Topics: 17-alpha-Hydroxyprogesterone; Adolescent; Adrenal Glands; Adrenal Hyperplasia, Congenital; Adult; Antley-Bixler Syndrome Phenotype; Child; Cosyntropin; Dehydroepiandrosterone; Dihydrotestosterone; Disorders of Sex Development; Female; Gonadal Dysgenesis, 46,XX; Humans; Infant, Newborn; Sex Differentiation; Steroid 11-beta-Hydroxylase; Steroid 21-Hydroxylase; Steroids; Virilism

Two siblings of Pakistani origin, karyotype 46 XY, were born with predominantly female external genitalia with minute phallus, bifid scrotum, urogenital sinus, and palpable gonads. The older sibling at the age of 8 days showed an adequate testosterone response to human chorionic gonadotrophin (hCG) stimulation. The diagnosis of 5 alpha-reductase deficiency was made at age 6 years when no 5 alpha-reduced glucocorticoid metabolites were detectable in urine even after tetracosactrin (Synacthen) stimulation. In the younger sibling the diagnosis of 5 alpha-reductase deficiency was provisionally made at the early age of 3 days on the basis of high urinary tetrahydrocortisol (THF)/allotetrahydrocortisol (5 alpha-THF) ratio and this ratio increased with age confirming the diagnosis. Plasma testosterone: dihydrotestosterone (DHT) ratio before and after hCG stimulation was within normal limits at age 3 days but was raised at age 9 months. Topical DHT cream application to the external genitalia promoted significant phallic growth in both siblings and in the older sibling corrective surgery was facilitated. In prepubertal male pseudohermaphrodites with normal or raised testosterone concentrations, phallic growth in response to DHT cream treatment could be an indirect confirmation of 5 alpha-reductase deficiency.

Topics: Administration, Topical; Cholestenone 5 alpha-Reductase; Cosyntropin; Dihydrotestosterone; Disorders of Sex Development; Humans; Infant, Newborn; Male; Ointments; Oxidoreductases; Tetrahydrocortisol

A child with ambiguous genitalia was born after an uncomplicated pregnancy. Laparotomy revealed intraabdominal hypoplastic testes containing normal appearing Leydig cells; germ cells were present in the left gonad, not in the right. The karyotype was 46,XY in blood leukocytes and in fibroblasts cultured from the gonads; there was no evidence of mosaicism. Endocrinologic study revealed no disorder of steroidogenesis. Androgen receptors were not studied. Serologic evaluation of blood leukocytes revealed the presence of H-Y antigen, but there are reasons to believe that less H-Y antigen was present in the cells of the patient than was present in corresponding cells from normal males. Gonadectomy and clitoral recession were performed at 3 weeks of age, and the patient was reared as a girl. We speculate that reduced expression of H-Y may have induced aberrant development of the gonads.

Topics: Cosyntropin; Cytotoxicity Tests, Immunologic; Disorders of Sex Development; H-Y Antigen; Humans; Hydrocortisone; Infant, Newborn; Karyotyping; Leukocytes; Male; Phenotype; Steroids

A true hermaphrodite with a bilateral ovotestis and a 46 XX karyotype was studied. This 14-year old subject developed ambiguous puberty with bilateral gynecomastia and stage IV public hair. Relatively high level of testosterone (T) (2.80 ng/ml), was found. The 5 alpha-reductase activity for T in the pubic skin was similar to that observed in normal adult males. A hemorrhagic corpus luteum in the left ovotestis was observed at laparotomy. The luteal phase immediately after dexamethasone administration (1 mg/day for 7 days) was characterized by a significant decrease of plasma androgens, T and androstenedione (A). The constantly low level of T (0.30 ng/ml) during the luteal phase in this subject did not appear to be due to the previously administered dexamethasone. This decrease of T production in the luteal phase might be secondary either to the increase of the estradiol-17 beta (E2) secreted by the corpus luteum or to the decrease of LH levels. Both mechanisms might act concomitantly.

Topics: Adolescent; Androgens; Androstenedione; Cosyntropin; Dehydroepiandrosterone; Dexamethasone; Disorders of Sex Development; Female; Follicle Stimulating Hormone; Genitalia, Male; Humans; In Vitro Techniques; Karyotyping; Luteal Phase; Luteinizing Hormone; Male; Ovary; Radioimmunoassay; Testis; Testosterone

Data are presented concerning a case of female pseudohermaphroditism of unknown etiology. The child was born with labioscrotal fusion and clitoromegaly. From the age of 5 to the age of 25 there was no clinical evidence of a hormonal abnormality. At the age of 25 the patient presented with masculinization and Cushing's syndrome, and a left adrenal tumor was removed. The patient was restudied at the age of 29, when 21-hydroxylase deficiency was excluded. Other types of congenital adrenal hyperplasia are considered unlikely. The possible relationship between the ambiguous genitalia present at birth and the virilizing tumor diagnosed at the age of 25 is analyzed.

Topics: 17-alpha-Hydroxyprogesterone; Adenoma; Adrenal Cortex Neoplasms; Adult; Age Factors; Cortodoxone; Cosyntropin; Disorders of Sex Development; Female; Humans; Hydrocortisone; Hydroxyprogesterones

In a 5-yr-old 46,XY male pseudohermaphrodite with microphallus, perineal hypospadias, chordee and cryptorchidism, serum C19 steroid levels were abnormally low in the basal state and after adrenal and testicular stimulation. Serum C21 steroid levels were elevated in the basal state and increased further after adrenal, but not after gonadal, stimulation. Urinary excretion of pregnanetriolone, a metabolite of 17-hydroxypregnenolone and 17-hydroxyprogesterone not normally present in the urine, was increased in the basal and stimulated states. Cortisol production was normal, and all steroid hormone levels were suppressed by dexamethasone. Testicular biopsy was consistent with prepubertal cryptorchid testes. Incubation of testicular tissue with labeled 17-hydroxyprogesterone revealed failure of conversion of precursor to androstenedione and testosterone. A significant increase in phallic length occurred after treatment with exogenous androgen. These findings are consistent with 17,20-desmolase deficiency in both gonads and adrenal glands.

Topics: Adolescent; Adult; Aldehyde-Lyases; Child; Child, Preschool; Chorionic Gonadotropin; Cosyntropin; Dexamethasone; Disorders of Sex Development; Humans; Infant; Male; Steroid 17-alpha-Hydroxylase; Steroids; Testosterone